A synthetic amino acid substitution of Tyr10 in A ss peptide sequence yields a dominant negative variant in amyloidogenesis

作者：Mazargui Honoree; Leveque Christian; Bartnik Dirk; Fantini Jacques; Gouget Tiphany; Melone Mariarosa A B; Funke Susanne A; Willbold Dieter; Perrone Lorena^*

来源：Aging Cell, 2012, 11(3): 530-541.

DOI：10.1111/j.1474-9726.2012.00814.x

• aggregation
• Alzheimer
• amyloid
• GM1
• oxidative stress
• rafts

Alzheimers disease (AD) is the most common cause of dementia in elderly people, and age is the major nongenetic risk factor for sporadic AD. A hallmark of AD is the accumulation of amyloid in the brain, which is composed mainly of the amyloid beta-peptide (A beta) in the form of oligomers and fibrils. However, how aging induces A beta aggregation is not yet fully determined. Some residues in the A beta sequence seem to promote A beta-induced toxicity in association with age-dependent risk factors for AD, such as (i) increased GM1 brain membrane content, (ii) altered lipid domain in brain membrane, (iii) oxidative stress. However, the role of A beta sequence in promoting aggregation following interaction with the plasma membrane is not yet demonstrated. As Tyr10 is implicated in the induction of oxidative stress and stabilization of A beta aggregation, we substituted Tyr 10 with a synthetic amino acid that abolishes A beta-induced oxidative stress and shows an accelerated interaction with GM1. This variant peptide shows impaired aggregation properties and increased affinity for GM1. It has a dominant negative effect on amyloidogenesis in vitro, in cellulo, and in isolated synaptosomes. The present study shed new light in the understanding of A beta-membrane interactions in A beta-induced neurotoxicity. It demonstrates the relevance of A beta sequence in (i) A beta-membrane interaction, underlining the role of age-dependent enhanced GM1 content in promoting A beta aggregation, (ii) A beta aggregation, and (iii) A beta-induced oxidative stress. Our results open the way for the design of peptides aimed to inhibit A beta aggregation and neurotoxicity.

• 出版日期2012-6